Infertility and subfertility represent major problems in domestic animals and humans. Our long-range goal is to discover and understand the hormonal, cellular, and molecular mechanisms regulating endometrial receptivity to implantation and uterine competency for establishment of pregnancy in order to provide fundamental information useful for diagnosis, prevention and treatment of fertility problems. The receptive endometrium represents a temporary, but unique physiological state of the uterus when conceptus (embryo and associated extraembryonic membranes) growth and implantation is possible. Inadequate endometrial receptivity affects conceptus growth, signaling for pregnancy recognition, and compromises implantation. Defects in endometrial receptivity cause pregnancy loss and thus fertility problems in both domestic animals and humans. The goal of this proposal is to better understand the biological and genetic mechanisms regulating endometrial receptivity and uterine competency for establishment and maintenance of pregnancy using an innovative large animal model combined with a systems biology approach. To achieve this goal, serial transfer of embryos will be conducted in beef heifers to select animals with intrinsic differences in early pregnancy loss. The selected animals will then be used in a series of experiments to uncover the physiological and genetic mechanisms governing endometrial receptivity and pregnancy success. Specific aims are to: (1) develop a unique animal resource to study endometrial receptivity and pregnancy loss using natural variation in fertility of beef heifers based on successful pregnancy outcomes; (2) investigate biological mechanisms governing endometrial receptivity and pregnancy loss; and (3) determine genetic mechanisms underlying endometrial receptivity and uterine competency for pregnancy. This research is innovative, because it will develop a unique animal model for the study of uterine biology and pregnancy. Completion of the research is expected to fill a substantial gap in our existing knowledge by providing novel insights into endometrial function, infertility and pregnancy loss. Translational outcomes of the research include biomarkers and selection tools for endometrial receptivity and uterine competency for pregnancy. In animal agriculture, the identified biomarkers are expected to provide diagnostic tools to identify and select heifers with superior endometrial receptivity an pregnancy success, which will increase production efficiency and profitability of cattle enterprises. In biomedicine, translation of the identified biomarkers to humans should provide novel indicators of endometrial receptivity that can be used to optimize assisted reproduction techniques and to diagnose treat and prevent infertility and pregnancy loss. PUBLIC HEALTH RELEVANCE: This research is expected to provide a better understanding of origins of infertility and pregnancy loss and improve assisted reproduction efficiency in both humans and domestic animals. The research should lead to new therapies to enhance pregnancy outcome in females conceiving naturally or via assisted reproduction technologies (ART) and to diagnose, treat and prevent infertility and recurrent pregnancy loss. Consequently, this research proposal has a dual benefit for the improvement of health and reproduction in both humans and agriculturally important animals.